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CLINICAL RESEARCH: ANTIPLATELET THERAPY

Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura

A Report From the SERF-TTP Research Group and the RADAR Project

Charles L. Bennett, MD, PhD^_*,_*, Benjamin Kim, MD^_*, Anaadriana Zakarija, MD^_*, Nicholas Bandarenko, MD, Dilip K. Pandey, MBBS, MS, PhD, Charlie G. Buffie, BA^_*, June M. McKoy, MD, MPH, JD^_*, Amul D. Tevar, MPH, John F. Cursio, MS, Paul R. Yarnold, PhD^_*, Hau C. Kwaan, MD, PhD, Davide De Masi^_*, Ravindra Sarode, MD^||, Thomas J. Raife, MD, Joseph E. Kiss, MD^¶, Dennis W. Raisch, PhD^_**, Charles Davidson, MD, FACC^_*, J. Evan Sadler, MD, PhD, Thomas L. Ortel, MD, PhD, X. Long Zheng, MD, PhD, Seiji Kato, PhD^¶¶, Masanori Matsumoto, MD, PhD^¶¶, Masahito Uemura, MD, PhD^¶¶ and Yoshihiro Fujimura, MD, PhD^¶¶

^_* VA Center for Management of Complex Chronic Care at Jesse Brown VA Medical Center, Divisions of Hematology/Oncology, Geriatric Medicine, Emergency Medicine, and Cardiology, Department of Medicine, and the Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois
University of North Carolina, Chapel Hill, North Carolina
Department of Neurology and Rehabilitation, University of Illinois Medical Center at Chicago, Chicago, Illinois
University of Iowa, Iowa City, Iowa
^¶ University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
^|| University of Texas Southwestern Medical Center, Dallas, Texas
^_** VA Cooperative Studies Program Clinical Research Pharmacy Coordinating Center, University of New Mexico, Albuquerque, New Mexico
Washington University, St. Louis, Missouri
Duke University Medical Center, Durham, North Carolina
The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania
^¶¶ Nara Medical University, Kashihara, Japan.

Manuscript received February 14, 2007; revised manuscript received April 5, 2007, accepted April 9, 2007.

^_* Address correspondence to: Dr. Charles L. Bennett, Associate Director, Midwest Center for Health Services and Policy Research, VA Chicago Healthcare System—Lakeside Division, Professor of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, 710 North Fairbanks Court, Olson Pavilion, Room 8250, Chicago, Illinois 60611. (Email: cbenne{at}northwestern.edu).

Objectives: We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).

Background: The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).

Methods: Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.

Results: Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.

Conclusions: Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.

Abbreviations and Acronyms   TPE = therapeutic plasma exchange   TTP = thrombotic thrombocytopenic purpura   VWF = von Willebrand factor